This invention relates to derivatives of 5,5-disubstituted pyrimidine-2,4,6-triones. These compounds show a marked antitumor and antimetastatic activity.
In normal tissue there is an equilibrium between synthesis and degradation. Extracellular matrix is degraded by proteinases which belong to at least three groups of matrix metalloproteinases. These are the collagenases, gelatinases and stromelysins. Normally there are specific inhibitors for these catabolic enzymes such as xcex12 macroglobulines and TIMP (=tissue inhibitor of metalloproteinases (MMP)) so that an excessive degradation of extracellular matrix does not occur. Adamalysins are a related group of proteinases. A prominent member of the adamalysins is TACE (TNF-xcex1-converting enzyme).
At least 17 different and yet highly homologous MMP species have been characterized, including the interstitial fibroblast collagenase (MMP-1, HFC), the neutrophil collagenase (MMP-8, HNC), two gelatinases, stromelysins (such as HSL-1) and HPUMP (for a recent review, see Birkedal-Hansen, H., Moore, W. G. I., Bodden, M. K., Windsor, L. J., Birkedal-Hansen; B., DeCarlo, A., Engler, J. A., Critical Rev. Oral Biol.Med. (1993) 4, 197-250. These proteinases share a number of structural and functional features but differ somewhat in their substrate specificity. Only HNC and HFC are capable of cleaving type I, II and III native triple-helical collagens at a single bond with the production of fragments xc2xe and xc2xc of the native chain length. This lowers the collagen melting point and makes them accessible to further attack by other matrix degrading enzymes.
However, the uncontrolled excessive degradation of this matrix is a characteristic of many pathological states such as e.g. in the clinical picture of rheumatoid arthritis, osteoarthritis and multiple sclerosis, in the formation of tumor metastases, corneal ulceration, inflammatory diseases and invasion and in diseases of bone and teeth.
It can be assumed that the pathogenesis of these clinical pictures can be favourably influenced by the administration of matrix metalloproteinase inhibitors. In the meantime a number of compounds are known from the literature (see e.g. the review article of D. E. Levy, A. M. Ezrin Emerging Drugs 2,205-230 (1997), M. Whittaker, P. Brown, Curr. Opin. Drug Discovery Dev. (1998), 1(2), 157-164. or are described in the patent literature, mainly with a hydroxamic acid residue, a thiol or phosphine group as a zinc binding group (see e.g. WO-A-9209563 by Glycomed, EP-A-497 192 by Hoffmann-LaRoche, WO-A-9005719 by British Biotechnology, EP-A-489 577 by Celltech, EP-A-320 118 by Beecham, U.S. Pat. No. 459 5700 by Searle, WO 97/20824 by Agouron Pharmaceuticals, WO 96/15096 by Bayer Corporation among others).
Some of these compounds show a high activity as inhibitors of matrix metalloproteinases but their oral availability is very low. Also such compounds often show broad spectrum inhibition of metalloproteinases which may be associated to undesired side-effects and toxicity.
Pyrimidine-2,4,6-trione derivatives have been described in EP0869947 generically as inhibitors of matrix metalloproteinases. However, there is still a high need for new compounds having low toxicity, no side-effects and a marked inhibitory activity against metallo-proteinases, especially as candidates for a chronic treatment against tumor growth and metastasis.
It has now been found that the claimed pyrimidine-2,4,6-trione derivatives have improved activity as matrix metallo-proteinase inhibitors over the compounds claimed in EP0869947 and also show good oral availability.
The present invention concerns compounds of the formula I 
in which
R1 represents a phenyl, phenoxy , phenylthio, phenylsulfmyl, phenylsulfonyl , phenylamino or phenylmethyl residue, wherein the phenyl moiety is unsubstituted or substituted by one or more halogen atoms, hydroxy, C1-C6 alkoxy, C1-C6 alkyl cyano, or nitro groups, and R2 represents an unsubstituted or substituted aryl or hetaryl group.
When the phenyl moiety of R1 is a substituted phenyl moiety, it is preferred that there are one or two substituents in the para and/or meta positions.
The present invention also encompasses pharmaceutically acceptable salts or prodrugs of the compounds of formula I as well as the use of these compounds to produce pharmaceutical agents.
It has now been found that the pyrimidine-2,4,6-trione derivatives of the present invention, have improved activity as matrix metallo-proteinase inhibitors over the compounds claimed in EP0869947 and also show good oral availability.
The aryl group of R2 consists of a phenyl ring. The hetaryl group is a cyclic unsaturated or saturated ring system consisting of 5 to 7 ring atoms which can be selected from one or more carbon, nitrogen, oxygen or sulfur atoms. Preferred are electron deficient hetaryl residues such as the nitrogen containing 6 membered rings like pyridines, pyrimidines, pyrazines or 1,3,5-triazines or its N-oxides. Most preferred are the hetaryl residues pyrimidinyl or pyrazinyl.
The aryl or hetaryl rings may be substituted by one or more substituents selected from halogen, hydroxy, alkoxy, amino, dialkylamino, cyano, lower alkyl, lower alkenyl, lower alkinyl, lower acyl, lower alkylthio, lower alkylsulfonyl, lower alkylaminocarbonyl, aminocarbonyl, SO2NR3R4, nitro, lower alkoxycarbonyl, carboxy, wherein R3 and R4, which can be the same or different represent hydrogen; C1-C6 alkyl, straight chained or branched, which can be substituted one or several times by OH, N(CH3)2 or which can be interrupted by oxygen, or represent CO R5, wherein R5 is an alkyl group which can be substituted by NH2. Preferred are substitutions in para and/or meta position by one to two of the above listed substituents.
Lower alkyl in residue R2 as such or in combinations with other residues denotes C1-C6-alkyl, preferred are methyl, ethyl, propyl, isopropyl or tert.-butyl.
Lower alkenyl denotes C2-C6 alkenyl, preferably allyl or pentadienyl. Lower alkinyl denotes C2-C6 alkinyl, preferably propargyl.
Lower acyl in the residue R2 above all denotes xe2x80x94C(O)xe2x80x94C1-C6-alkyl or xe2x80x94C(O)H, preferred for an acetyl group.
The alkyl residues in R2, can optionally be interrupted once or several times by heteroatoms (O, S, NH).
Halogen is understood as fluorine, chlorine, bromine, iodine, preferably chlorine or bromine.
If compounds of the formula I contain one or several asymmetric carbon atoms, the optically active compounds of the formula I are also a subject matter of the present invention.
Compounds of the formula I can be synthesized by well-known processes preferably in that compounds of the formula II 
in which R1 has the above-mentioned meaning and T represents a leaving group such as Hal or OSO2R3 Hal denoting chlorine, bromine or iodine and R3, denoting an aryl or a methyl residue, are reacted with a compound of the formula III 
in which R2 has the meaning stated above and optionally converted into pharmaceutically acceptable salts.
Compounds of the formula II can be synthesized by analogy to known literature procedures. Thus for example pyrimidine-2,4,6-triones brominated in the 5-position can be synthesized by reacting the appropriate bromomalonic acid dialkyl esters with urea (e.g. Acta Chim. Acad. Sci. Hung. 107 (2), 139 (1981)). The corresponding brominated or chlorinated compounds of the formula II can be obtained by reacting pyrimidine-2,4,6-triones substituted by R1-Phenyl in the 5-position with bromine (analogous to J. Prakt. Chemie 136, 329 (1933) or J. Chem. Soc. 1931, 1870) or sulfuryl chloride (J. Chem. Soc. 1938, 1622) or N-bromo-succinimide or similar brominating agents. Such procedures are also described in EP0869947.
Amines of the formula III are commercially available or are usually known in the literature or in analogy to the described methods in the experimental part.
Pyrimidine-2,4,6-triones of formula II with T representing hydrogen can be prepared according to known methods by reacting malonic acid esters with urea (see for example J. Med. Chem. 10, 1078 (1967) or Helvetica Chim. Acta 34, 459 (1959), Pharmacie 38 (1), 65 (1983)) or EP0869947. The reactions are usually carried out in alcohols such as methanol, ethanol or butanol in the presence of an appropriate sodium alcoholate at temperatures between 40xc2x0 C. and 100xc2x0 C.
The malonic acid esters which are needed for the preparation of pyrimidine-2,4,6-triones are known from the literature or can be produced according to processes known from the literature. A convenient process for the preparation of malonic acids where R1 has the above mentioned meaning is described in the following scheme: 
Examples for these reactions can be found in Houben-Weyl Vol E5/2, J. Org. Chem. 46, 2999 (1981) and Arch. Pharm. 323, 579 (1990).
Compounds of the formula I can contain one or several chiral centres and can then be present in a racemic or in an optically active form. The racemates can be separated according to known methods into the enantiomers. Preferably diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid or with an optically active amine such as e.g. D- or L-xcex1-phenyl-ethylamine, ephedrine, quinidine or cinchonidine.
Alkaline salts, earth alkaline salts like Ca or Mg salts, ammonium salts, acetates or hydrochlorides are mainly used as pharmaceutically acceptable salts which are produced in the usual manner e.g. by titrating the compounds with inorganic or organic bases or inorganic acids such as e.g. sodium hydroxide, potassium hydroxide, aqueous ammonia, C1-C4-alkyl-amines such as e.g. triethylamine or hydrochloric acid. The salts are usually purified by reprecipitation from water/acetone.
The compounds of formula I and salts thereof according to the invention can be administered enterally or parenterally in a liquid or solid form. In this connection all the usual forms of administration come into consideration such as for example tablets, capsules, coated tablets, syrups, solutions, suspension etc. Water which contains additives such as stabilizers, solubilizers and buffers that are usual in injection solutions is preferably used as the injection medium.
Such additives are e.g. tartrate and citrate buffer, ethanol, complexing agents (such a ethylenediaminetetra-acetic acid and non-toxic salts thereof), high-molecular polymers (such as liquid polyethylene oxide) to regulate viscosity. Liquid carrier substances for injection solutions have to be sterile and are preferably dispensed into ampoules. Solid carrier substances are e.g. starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acids, higher molecular fatty acids (such as stearic acid), gelatins, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers (such as polyethylene glycols); suitable preparations for oral application can optionally also contain flavourings and sweeteners.
The dosage depends on various factors such as manner of administration, species, age and/or individual state of health. The doses to be administered daily are about 10-1000 mg/human, preferably 100-500 mg/human and can be taken singly or distributed over several administrations.
Prodrugs of the compounds of the invention are such which are converted in vivo to the pharmacological active compound. The most common prodrugs are carboxylic acid esters.